SYNAPTOTAGMIN-9 IN MOUSE RETINA.

Synaptotagmin-9 (Syt9) is a Ca2+ sensor mediating fast synaptic release expressed in various parts of the brain. The presence and role of Syt9 in retina is unknown. We found evidence for Syt9 expression throughout the retina and created mice to conditionally eliminate Syt9 in a cre-dependent manner. We crossed Syt9fl/fl mice with Rho-iCre, HRGP-Cre, and CMV-cre mice to generate mice in which Syt9 was eliminated from rods (rodSyt9CKO), cones (coneSyt9CKO), or whole animals (CMVSyt9). CMVSyt9 mice showed an increase in scotopic electroretinogram (ERG) b-waves evoked by bright flashes with no change in a-waves. Cone-driven photopic ERG b-waves were not significantly different in CMVSyt9 knockout mice and selective elimination of Syt9 from cones had no effect on ERGs. However, selective elimination from rods decreased scotopic and photopic b-waves as well as oscillatory potentials. These changes occurred only with bright flashes where cone responses contribute. Synaptic release was measured in individual rods by recording anion currents activated by glutamate binding to presynaptic glutamate transporters. Loss of Syt9 from rods had no effect on spontaneous or depolarization-evoked release. Our data show that Syt9 is acts at multiple sites in the retina and suggest that it may play a role in regulating transmission of cone signals by rods.

Bayesian borrowing for basket trials with longitudinal outcomes.

Basket trials are a novel clinical trial design in which a single intervention is investigated in multiple patient subgroups, or "baskets." They offer the opportunity to share information between subgroups, potentially increasing power to detect treatment effects. Basket trials offer several advantages over running a series of separate trials, including reduced sample sizes, increased efficiency, and reduced costs. Primarily, basket trials have been undertaken in Phase II oncology settings, but could be a promising design in other areas where a shared underlying biological mechanism drives different diseases. One such area is chronic aging-related diseases. However, trials in this area frequently have longitudinal outcomes, and therefore suitable methods are needed to share information in this setting. In this paper, we extend three Bayesian borrowing methods for a basket design with continuous longitudinal endpoints. We demonstrate our methods on a real-world dataset and in a simulation study where the aim is to detect positive basketwise treatment effects. Methods are compared with standalone analysis of each basket without borrowing. Our results confirm that methods that share information can improve power to detect positive treatment effects and increase precision over independent analysis in many scenarios. In highly heterogeneous scenarios, there is a trade-off between increased power and increased risk of type I errors. Our proposed methods for basket trials with continuous longitudinal outcomes aim to facilitate their applicability in the area of aging related diseases. Choice of method should be made based on trial priorities and the expected basketwise distribution of treatment effects.

Looking for "us": power reimagined in mathematics learning for Black communities in the pandemic.

In this reflective essay, a BlackCrit lens is used to explore new and evolving possibilities for Black teachers, families, leaders, and students in ways that highlight and honor parents' agency, expand notions of digital equity in mathematics, and preview new and re-prioritized approaches which aid liberatory mathematics, teaching, and learning spaces that resurfaced in the pandemic. Several actions reimagine the work of mathematics as building blocks for engaging the flourishing for Black communities: (1) expanding and amplifying direct networks for Black parents to share, communicate, and advocate for their own needs and spaces around mathematics; (2) making visible and amplifying our advocacy for racial justice in the content creation and representation found in current digital platforms for meeting the needs of Black communities; and the need to (3) invest in, prioritize usage of, and illuminate mathematics commercial and academic entities focused solely on creating content and centering Black (and other people's) knowledge and experiences in mathematics for Black families.

Accuracy of pedicle localization using a 3D ultrasound navigator on vertebral phantoms for posterior spinal surgery.

Severe adolescent idiopathic scoliosis (AIS) requires surgery to halt curve progression. Accurate insertion of pedicle screws is important. This study reports a newly developed 3D ultrasound (3DUS) to localize pedicles intraoperatively and register a pre-op 3D vertebral model to the surface to be displayed for navigation. The objective was to determine speed of the custom 3DUS navigator and accuracy of pedicle probe placement. The developed 3DUS navigator integrated an ultrasound scanner with motion capture cameras. Two adolescent 3D printed spine models T2-T8 and T7-T11 were modified to include pedicle holes with known trajectory and be mounted on a high precision LEGO pegboard in a water bath for imaging. Calibration of the motion cameras and the 3DUS were conducted prior to the study. A total of 27 scans from T3 to T11 vertebrae with 3 individual scans were performed to validate the repeatability. Three accuracy tests that varied vertebral a) orientation, b) position and c) a combination of location and orientation were completed. Based on all experiments, the acquisition-to-display time was 18.9±3.1s. The repeatability of the trajectory error and positional error were 0.5±0.2° and 0.3±0.1mm, respectively. The a) center orientation, b) position and c) orientation/position on trajectory and positional error were for a) 1.4±0.9° and 0.5±0.4mm, b) 1.4±0.8° and 0.3±0.3mm and c) 2.0±0.8° and 0.5±0.5mm, respectively. These results demonstrated that a high precision real-time 3DUS navigator for screw placement in scoliosis surgery is feasible. The next step will study the effect of surrounding soft tissues on navigation accuracy.

Validation of a novel handheld 3D ultrasound system for imaging scoliosis - phantom study.

Use of 3D ultrasound (US) scanners to detect and monitor scoliosis have been validated. The Cobb angle, axial vertebral rotation, spinal flexibility, curvatures in the sagittal profile and the Cobb angle on the plane of maximum curvature (PMC) can be measured from coronal, transverse and sagittal planes of ultrasound images. However, traditional 3D ultrasound scanners are relatively bulky and expensive. 2D US handheld and low-cost scanners are widely available. To adapt the 2D scanners for scoliosis applications, a position and orientation system is integrated with the scanner. The objective of this study was to validate a newly developed 3D handheld US system to image the spine. The wireless handheld US scanner (C3-HD, Clarius, Canada) was selected because of its high resolution and availability of raw data. A wireless tracking system based on electromagnetic (G4 system, Polhemus, USA) was integrated with the Clarius ultrasound. During scanning, the ultrasound information was synchronized with the scanner's position and orientation by using custom developed software. Both information were streamed wirelessly to a laptop. Custom software reconstructed and displayed the 3D spinal image in real-time. A single 3D printed vertebra, two full plastic spine phantoms from T1-T12 vertebrae and a non-scoliotic volunteer were scanned. The 3D reconstruction process of a spine image was less than 3 seconds. The dimensional and the angle errors were 1 mm and 3°, respectively. This study demonstrated that a low-cost ($11,000 USD) handheld 3D ultrasound system was developed and validated. Clinical trials on subjects attending will be the next step.

Distinct genomic landscapes of gastroesophageal adenocarcinoma depending on PD-L1 expression identify mutations in RAS-MAPK pathway and TP53 as potential predictors of immunotherapy efficacy.

BACKGROUND: The impact of molecular alterations on programmed death-ligand 1 (PD-L1) combined positive score (CPS) is not well studied in gastroesophageal adenocarcinomas (GEAs). We aimed to characterize genomic features of tumors with different CPSs in GEAs. PATIENTS AND METHODS: Genomic alterations of 2518 GEAs were compared in three groups (PD-L1 CPS ≥ 10, high; CPS = 1-9, intermediate; CPS < 1, low) using next-generation sequencing. We assessed the impact of gene mutations on the efficacy of immune checkpoint inhibitors (ICIs) and tumor immune environment based on the Memorial Sloan Kettering Cancer Center and The Cancer Genome Atlas databases. RESULTS: High, intermediate, and low CPSs were seen in 18%, 54% and 28% of GEAs, respectively. PD-L1 positivity was less prevalent in women and in tissues derived from metastatic sites. PD-L1 CPS was positively associated with mismatch repair deficiency/microsatellite instability-high, but independent of tumor mutation burden distribution. Tumors with mutations in KRAS, TP53, and RAS-mitogen-activated protein kinase (MAPK) pathway were associated with higher PD-L1 CPSs in the mismatch repair proficiency and microsatellite stability (pMMR&MSS) subgroup. Patients with RAS-MAPK pathway alterations had longer overall survival (OS) from ICIs compared to wildtype (WT) patients [27 versus 13 months, hazard ratio (HR) = 0.36, 95% confidence interval (CI): 0.19-0.7, P = 0.016] and a similar trend was observed in the MSS subgroup (P = 0.11). In contrast, patients with TP53 mutations had worse OS from ICIs compared to TP53-WT patients in the MSS subgroup (5 versus 21 months, HR = 2.39, 95% CI: 1.24-4.61, P = 0.016). CONCLUSIONS: This is the largest study to investigate the distinct genomic landscapes of GEAs with different PD-L1 CPSs. Our data may provide novel insights for patient selection using mutations in TP53 and RAS-MAPK pathway and for the development of rational combination immunotherapies in GEAs.

Alveolar Bone Segmentation in Intraoral Ultrasonographs with Machine Learning.

The use of intraoral ultrasound imaging has received great attention recently due to the benefits of being a portable and low-cost imaging solution for initial and continuing care that is noninvasive and free of ionizing radiation. Alveolar bone is an important structure in the periodontal apparatus to support the tooth. Accurate assessment of alveolar bone level is essential for periodontal diagnosis. However, interpretation of alveolar bone structure in ultrasound images is a challenge for clinicians. This work is aimed at automatically segmenting alveolar bone and locating the alveolar crest via a machine learning (ML) approach for intraoral ultrasound images. Three convolutional neural network-based ML methods were trained, validated, and tested with 700, 200, and 200 images, respectively. To improve the robustness of the ML algorithms, a data augmentation approach was introduced, where 2100 additional images were synthesized through vertical and horizontal shifting as well as horizontal flipping during the training process. Quantitative evaluations of 200 images, as compared with an expert clinician, showed that the best ML approach yielded an average Dice score of 85.3%, sensitivity of 88.5%, and specificity of 99.8%, and identified the alveolar crest with a mean difference of 0.20 mm and excellent reliability (intraclass correlation coefficient ≥0.98) in less than a second. This work demonstrated the potential use of ML to assist general dentists and specialists in the visualization of alveolar bone in ultrasound images.

Occupational therapy for adults with brain tumors in the acute care setting.

The number of adults diagnosed with brain tumors is increasing, as are the survival rates. Neurological impairments from brain tumors can impact activity and participation. Adults with brain tumors benefit from post-acute rehabilitation. However, there is limited evidence from the acute care setting. The purpose of this study was to examine how acute care occupational therapy services were utilized and whether patients made functional gains after receiving occupational therapy services. A retrospective chart review of 153 electronic medical records was completed for patients who received occupational therapy services at a large teaching hospital. Data collected included number of occupational therapy visits, the types of interventions, and patient performance using the Boston University Activity Measure for Post-Acute Care "6 Clicks for Daily Activity" short form (AM-PAC). More than half the patients received one occupational therapy visit (54.2%) with a median length of stay of three days. Most interventions focused on activities of daily living (ADLs). Of those patients who received more than one visit, 67% showed improvements in their AM-PAC scores. Occupational therapy practitioners provided interventions that addressed ADLs, and patients demonstrated gains in functional performance. These findings suggest that patients benefit from occupational therapy services provided in the acute care setting.

Role of MAPK in oncolytic herpes viral therapy in triple-negative breast cancer.

Triple-negative breast cancers (TNBCs) have poor clinical outcomes owing to a lack of targeted therapies. Activation of the MEK/MAPK pathway in TNBC has been associated with resistance to conventional chemotherapy and biologic agents and has a significant role in poor clinical outcomes. NV1066, a replication-competent herpes virus, infected, replicated in and killed all TNBC cell lines (MDA-MB-231, HCC1806, HCC38, HCC1937, HCC1143) tested. Greater than 90% cell kill was achieved in more-sensitive lines (MDA-MB-231, HCC1806, HCC38) by day 6 at a multiplicity of infection (MOI) of 0.1. In less-sensitive lines (HCC1937, HCC1143), NV1066 still achieved >70% cell kill by day 7 (MOI 1.0). In vivo, mean volume of flank tumors 14 days after treatment with NV1066 was 57 versus 438 mm(3) in controls (P=0.002). NV1066 significantly downregulated p-MAPK activation by 48 h in all cell lines in vitro and in MDA-MB-231 xenografts in vivo. NV1066 demonstrated synergistic effects with a MEK inhibitor, PD98059 in vitro. We demonstrate that oncolytic viral therapy (NV1066) effectively treats TNBC with correlation to decreased MEK/MAPK signaling. These findings merit future studies investigating the potential role of NV1066 as a sensitizing agent for conventional chemotherapeutic and biologic agents by downregulating the MAPK signaling pathway.

Bevacizumab continuation beyond initial bevacizumab progression among recurrent glioblastoma patients.

BACKGROUND: Bevacizumab improves outcome for most recurrent glioblastoma patients, but the duration of benefit is limited and survival after initial bevacizumab progression is poor. We evaluated bevacizumab continuation beyond initial progression among recurrent glioblastoma patients as it is a common, yet unsupported practice in some countries. METHODS: We analysed outcome among all patients (n=99) who received subsequent therapy after progression on one of five consecutive, single-arm, phase II clinical trials evaluating bevacizumab regimens for recurrent glioblastoma. Of note, the five trials contained similar eligibility, treatment and assessment criteria, and achieved comparable outcome. RESULTS: The median overall survival (OS) and OS at 6 months for patients who continued bevacizumab therapy (n=55) were 5.9 months (95% confidence interval (CI): 4.4, 7.6) and 49.2% (95% CI: 35.2, 61.8), compared with 4.0 months (95% CI: 2.1, 5.4) and 29.5% (95% CI: 17.0, 43.2) for patients treated with a non-bevacizumab regimen (n=44; P=0.014). Bevacizumab continuation was an independent predictor of improved OS (hazard ratio=0.64; P=0.04). CONCLUSION: The results of our retrospective pooled analysis suggest that bevacizumab continuation beyond initial progression modestly improves survival compared with available non-bevacizumab therapy for recurrent glioblastoma patients require evaluation in an appropriately randomised, prospective trial.

A cross-sectional assessment of stroke rehabilitation in Nebraska hospitals.

OBJECTIVE: To assess the structure and process of stroke rehabilitation in Nebraska hospitals. DESIGN: Cross-sectional mail survey using the Dillman tailored-design method of administration. SETTING: Hospitals in Nebraska. PARTICIPANTS: Approximately 77% of the 84 Nebraska hospitals that provide stroke rehabilitation are critical access hospitals (CAHs) that are limited to 25 beds. Our study sample of hospitals (N=53) included the 19 hospitals licensed for 47 to 689 beds (non-CAHs) and a stratified random sample of 34 of the 65 CAHs. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Self-reported stroke rehabilitation team structure and processes, purposes of and barriers to the use of evidence-based standardized assessments, specific assessments used, and access to specialized stroke rehabilitation services and community resources. RESULTS: Thirty-six (68%) of the 53 hospitals responded to the survey. Approximately 61% of the hospitals used an organized team to provide stroke rehabilitation; 8% of the hospitals-all non-CAHs-had a team dedicated to stroke rehabilitation. After adjusting for hospital size, having an organized team was significantly associated with the use of standardized assessments to improve communication, measure progress and outcomes, evaluate effectiveness of practice, and compare patient outcomes across conditions. Access to specialized stroke rehabilitation professionals and services was significantly greater in non-CAHs. CONCLUSIONS: Hospital size and the presence of a team are determinants of the structure and process of stroke rehabilitation in Nebraska hospitals. Further research is needed to determine (1) whether team structure is a determinant of stroke rehabilitation outcomes across the continuum of care settings, (2) the needs of rural stroke survivors, and (3) whether technology can facilitate the use of stroke rehabilitation standardized assessments by rural health care professionals.

Effectiveness of interventions to prevent falls in people with Alzheimer's disease and related dementias.

A systematic review was conducted to determine the effectiveness of interventions to prevent falls in people with Alzheimer's disease (AD) and related dementias. Twelve research reports met inclusion criteria. Studies reported on three types of intervention: (1) exercise- and motor-based interventions, (2) nursing staff-directed interventions, and (3) multidisciplinary interventions. Strategies were offered as single or multifaceted intervention programs. All types of intervention resulted in benefit, although the evidence for effectiveness is tentative because of the studies' limitations. More research is needed to better understand appropriate dosages of intervention. No evidence was found for the effectiveness of prevention programs accessed as part of occasional respite care. Occupational therapy was seldom involved in the interventions researched. Because effective fall prevention programs are embedded in people's daily routines and encouraged participation in occupation, the contribution occupational therapy practitioners can make to the care of people with AD has yet to be fully realized.

Identifying the best surface topography parameters for detecting idiopathic scoliosis curve progression.

There is no consensus on which surface topography (ST) parameters may be used to detect scoliosis progression. The sensitivity to change of common ST parameters has not yet been compared. The goal of this study was to determine which ST parameters are most sensitive to scoliosis progression in patients with adolescent idiopathic scoliosis (AIS) receiving conservative treatment. Fifty-eight subjects with AIS were included whose Cobb angle had progressed by at least 5 degrees during a 1 year interval. All had had ST scans and frontal radiographs at a 12 month interval at our clinic. Commonly used back-only ST parameters and contributing scores were derived by one evaluator. Standardized response mean (SRM) and 95% confidence intervals (CI) were calculated using the absolute value of the changes between baseline and follow-up to reflect change in deformity, independent of direction. Decompensation, cosmetic score, Deformity in the Axial Plane Index (DAPI), trunk rotation, Hump Sum, and lordosis angle were highly sensitive to scoliosis progression (SRM>0.8). Cosmetic score, Posterior Trunk Symmetry Index (POTSI), and kyphosis angle had significantly poorer SRM values than the Cobb angle. All other ST parameters had SRM estimates that did not differ significantly from the Cobb angle, suggesting that they have a similar ability to detect progression The ST measures that were most sensitive to detection of scoliosis progression in the frontal, transverse, and sagittal planes were decompensation, trunk rotation, and lordosis angle, respectively. Absolute changes in surface parameters representing either worsening or improvement externally could reflect worsening of the internal deformity. The majority of ST parameters are potentially sensitive to scoliosis progression.

Computer-assisted Cobb angle measurement on posteroanterior radiographs.

The Cobb angle method is the gold standard to assess severity of scoliosis. A computer-aided method was developed to provide a semi-automatic Cobb angle measurement during a scoliosis clinic. This study was to evaluate the reliability and accuracy of the developed method. Curve types were also tested. The computer method required enhancement of the contrast, normalization of the image size, and selection of the end-vertebrae on the radiographs before the automatic measurement started. The computer-aided process automatically identified the line segments that fitted to the endplates of the end-vertebrae. The Cobb angle was then calculated from the slopes of these lines. Seventy-six radiographs were randomly selected and categorized with Lenke's classification. Among them, 75 cases were used and categorized into 4 types: 1, 3, 5 and 6. One type 2 case was excluded. An orthopedic spine surgeon measured the radiographs manually, serving as the reference standard. Two observers used the developed method and measured twice. For each curve type, the inter-method, inter-observer, and intra-observer variability were analyzed by Intraclass correlation coefficients (ICC[2,1]). The ICC values were higher than 0.90 in all these types. The developed method was reliable to measure the Cobb angle and was not dependent on the curve type.

Can future back pain in AIS subjects be predicted during adolescence from the severity of the deformity?

Back pain is frequently reported as a symptom of adolescent idiopathic scoliosis (AIS). Prediction of pain in adulthood would be useful to identify subjects requiring follow-up. The aim is to determine adolescent predictors of adult back pain. This study is a retrospective review of 27 females with AIS who attended our pediatric scoliosis clinic and later completed the SRS-22 questionnaire as young adults (range 18-25 years). Subjects with surgery at baseline (age 14-16 years) were excluded. The relationships between largest curve size, decompensation and trunk twist at baseline and pain as measured by the SRS-22 pain domain as young adults were studied. At baseline, subjects had a largest curve of 47+/-15 degrees , decompensation of 18+/-14 mm and trunk twist of 14+/-6 degrees . At follow-up, 5.3+/-1.9 years later, the total SRS-22 score was 3.9+/-0.3 and the pain domain score was 3.9+/-0.7. Pearson correlations between the SRS-22 pain domain and largest curve, decompensation and trunk twist were 0.17, -0.11 and -0.25, respectively (p>0.05). Individual questions within the pain domain had similar correlations. Even though the sample represented a wide range of scoliosis severity at baseline and a wide range of pain scores (2.4 to 5) at follow-up, baseline scoliosis deformity parameters of largest curve size, decompensation and trunk twist did not predict scoliosis-related pain in young adulthood.

Preliminary validation of curve progression model for brace treatment.

Brace treatment is the most commonly used non-surgical treatment for adolescent idiopathic scoliosis (AIS). A brace compliance monitoring system consisting of a microcomputer and a force transducer was used to monitor how brace candidates used their braces during daily activates. A prediction model of the brace treatment outcome was developed based on 20 AIS subjects. Six subjects (1M, 5F) with AIS who had worn their braces for six weeks participated into this study. One month data was recorded during the study period. Knowing the risk progression at the beginning of brace treatment plus how brace subjects used their braces in terms of brace tightness and wear time during brace treatment yielded a predicted outcome which was compared to the final treatment outcomes with 2 years followed-up. This preliminary result demonstrated that the prediction model was able to predict the treatment outcome within +/-3.5 degrees.

Development of a MEMS-based sensor array to characterise in situ loads during scoliosis correction surgery.

Finite element analysis was implemented in three stages to design a piezoresistive, micro-electro-mechanical systems sensor array consisting of four-terminal sensors placed on deformable silicon diaphragms. This sensor array was used to retrofit the Contrel-Dubousset instrumentation in order to capture forces and moments applied by surgeons in real time during scoliosis correction surgery. Outputs from the sensor array have been designed to be compatible with a low-power wireless data transmission system that is currently being developed with a collaborating team in the biomedical industry. The designed sensor array is capable of resolving forces of up to 1000 N and moments of up to 4000 N mm in three dimensions during surgery. A process flow to produce the first prototyped version of this micro sensor with known performance characteristics is presented and tested. Acceptable correlation was found between the performance of the manufactured prototypes, numerical simulation and similar documented devices.

A wireless personal wearable network system to understand the biomechanics of orthotic for the treatment of scoliosis.

The wear tightness of an orthosis for the treatment of scoliosis varies greatly during daily activities. Currently, there is no commercially available product that can monitor force distribution inside the brace and the time that the othosis is worn during daily activities. Subjective feeling is the most commonly used method. To provide an objective measure, a battery-powered wireless personal wearable network system is developed. This system consists of up to 16 wireless force loggers and a USB ZigBee dongle. Each logger contains a force sensor and a wireless unit. The whole system records how much time the orthosis has been used and how loads distribute inside the orthoses. Laboratory tests have been performed; the maximum force measurement error is +/-0.02N and the resolution is 0.1N. The average power consumption of the system is 0.3mW/h and thus a single AAA-sized alkaline battery is able to support the power for 6 months.

An oncolytic mutant of herpes simplex virus type-1 in which replication is governed by a promoter/enhancer of human papillomavirus type-16.

Although herpes simplex virus type-1 (HSV-1) can be used as an oncolytic virus it has the undesirable side effect of neurotoxicity. To create a virus with improved specificity for oral cancer we used a fragment of human papillomavirus type-16, which is frequently found in oral and cervical cancers, but not elsewhere. The upstream regulatory region, URR16, was shown to have a high level of transcriptional activity in three of four oral cancer cell lines but low activity in three cell lines derived from brain cancers. URR16 was therefore placed in HSV-1, replacing the promoter of the essential gene ICP4, and the resulting virus was named HSPV-1. When cells were infected with HSPV-1, ICP4 was expressed at levels that were not associated with the level of activity of URR16. The virus replicated in each type of cell to a final titer that showed a correlation with the level of expression of ICP4, but with no correlation to either the tumor of origin or the presence of HPV sequences in the cells. To find if some function of HSV-1 was affecting the activity of URR16, oral cancer cells were transfected with a URR-reporter construct and were then infected with virus. This induced transcription, which was attributed to immediate-early viral genes other than ICP4. A promoter/enhancer from a papillomavirus therefore has the potential to regulate the functions of an oncolytic strain of HSV-1, and is affected by functions of both the host cell and of HSV-1 itself.